rs17231436

Variant names:

• chrX-116173953-G-C
• rs17231436
• NM_000686.5:c.*581G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000686.5(AGTR2):​c.*581G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0102 in 124,380 control chromosomes in the GnomAD database, including 14 homozygotes. There are 352 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.011 (14 hom., 352 hem., cov: 23)
  • Exomes 𝑓: 0.000079 (0 hom. 0 hem.)
• Consequence: AGTR2 NM_000686.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0640
• Publications: 2 publications found

Genes affected

AGTR2 (HGNC:338): (angiotensin II receptor type 2) The protein encoded by this gene belongs to the G-protein coupled receptor 1 family, and functions as a receptor for angiotensin II. It is an intergral membrane protein that is highly expressed in fetus and in neonates, but scantily in adult tissues, except brain, adrenal medulla, and atretic ovary. This receptor has been shown to mediate programmed cell death and this apoptotic function may play an important role in developmental biology and pathophysiology. Mutations in this gene are been associated with X-linked cognitive disability. Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV) and SARS-CoV-2 infection results in down-regulation of angiotensin converting enzyme-2 (ACE2) receptors, the effects of which, triggers serious inflammatory lesions in the tissues involved, primarily in the lungs. The inflammatory reaction appears to be mediated by angiotensin II derivatives, including the angiotensin AT2 receptor which has been found to be upregulated in bronchoalveolar lavage samples from Coronavirus disease 2019 (COVID19) patients. [provided by RefSeq, Jul 2020]

AGTR2 Gene-Disease associations (from GenCC):

• non-syndromic X-linked intellectual disability

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet
• X-linked complex neurodevelopmental disorder

  Inheritance: XL Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0113 (1268/111783) while in subpopulation AFR AF = 0.0389 (1201/30878). AF 95% confidence interval is 0.0371. There are 14 homozygotes in GnomAd4. There are 352 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGTR2	NM_000686.5	c.*581G>C		3_prime_UTR_variant	Exon 3 of 3	ENST00000371906.5	NP_000677.2
AGTR2	NM_001385624.1	c.*581G>C		3_prime_UTR_variant	Exon 2 of 2		NP_001372553.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGTR2	ENST00000371906.5	c.*581G>C		3_prime_UTR_variant	Exon 3 of 3	1	NM_000686.5	ENSP00000360973.4

Frequencies

GnomAD3 genomes AF: 0.0113 AC: 1267 AN: 111733 Hom.: 14 Cov.: 23

Gnomad AFR AF: 0.0389

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00477

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000366

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00426

Gnomad NFE AF: 0.0000754

Gnomad OTH AF: 0.00797

GnomAD4 exome AF: 0.0000794 AC: 1 AN: 12597 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 3615

African (AFR) AF: 0.00 AC: 0 AN: 6

American (AMR) AF: 0.00322 AC: 1 AN: 311

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8

East Asian (EAS) AF: 0.00 AC: 0 AN: 28

South Asian (SAS) AF: 0.00 AC: 0 AN: 93

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 11113

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 920

Other (OTH) AF: 0.00 AC: 0 AN: 116

GnomAD4 genome AF: 0.0113 AC: 1268 AN: 111783 Hom.: 14 Cov.: 23 AF XY: 0.0103 AC XY: 352 AN XY: 34013

African (AFR) AF: 0.0389 AC: 1201 AN: 30878

American (AMR) AF: 0.00477 AC: 50 AN: 10488

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2646

East Asian (EAS) AF: 0.00 AC: 0 AN: 3545

South Asian (SAS) AF: 0.00 AC: 0 AN: 2720

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6018

Middle Eastern (MID) AF: 0.00467 AC: 1 AN: 214

European-Non Finnish (NFE) AF: 0.0000754 AC: 4 AN: 53060

Other (OTH) AF: 0.00787 AC: 12 AN: 1525

Alfa AF: 0.00890 Hom.: 32

Bravo AF: 0.0136

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.7
DANN	Benign	0.60
PhyloP100		0.064
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs17231436; hg19: chrX-115305206;